Bupropion to treat herpes viral diseases

ABSTRACT

Methods are disclosed for the treatment of a herpes viral infection in a human or animal subject by administering bupropion or a physiologically acceptable salt, solvate or enantiomer thereof. Most particularly, the virus is HSV1 or HSV2.

This application claims the benefit of Provisional application No.60/135,494, filed Dec. 8, 1998 now abandoned.

FIELD OF THE INVENTION

This invention relates to a new medical use for bupropion andphysiologically acceptable salts and solvates thereof. Specifically theinvention concerns the use of bupropion in treating viral infections,more particularly infections caused by viruses of the Herpes family.

BACKGROUND OF THE INVENTION

Bupropion hydrochloride,(±)-1-(3-chlorophenyl)-2-[(1,1-di-methylethyl)-amino]-1-propanonehydrochloride has been used for the treatment of depression. Bupropionis a relatively weak inhibitor of the neuronal uptake of noradrenaline(NA), serotonin and dopamine (DA), and does not inhibit monoamineoxidase. While the mechanism of action of bupropion, as with otherantidepressants, is unknown, it is presumed that this action is mediatedby noradrenergic and/or dopaminergic mechanisms. Available evidencesuggests that bupropion is a selective inhibitor of noradrenaline (NA)at doses that are predictive of antidepressant activity in animalmodels. See Ascher, J. A., et al., Bupropion: A Review of its Mechanismof Antidepressant Activity. Journal of Clinical Psychiatry, 56: p.395-401,1995.

It has also been disclosed that bupropion is useful for the treatment ofmigraine (U.S. Pat. No. 5,753,712), reducing cholesterol (U.S. Pat. No.4,438,138), treatment of minimal brain dysfunction (U.S. Pat. No.4,435,449), treatment of tardive dyskinesia (U.S. Pat. No. 4,425,363),reversing impaired mental alertness due to ethanol consumption (U.S.Pat. No. 4,393,078), treatment of psychosexual dysfunction (U.S. Pat.No. 4,507,323), suppressing prolactin secretion (U.S. Pat. No.4,347,257) and as an aid to smoking cessation.

The Herpes family of viruses is responsible for a wide range ofinfectious diseases in several species, including chicken pox, shingles,retinitis, pneumonitis and keratitis in humans and diseases of the skinand mucosa, including keratitis in rabbits, herpetic encephalitis inmice, Herpes viruses include Herpes zoster, HSV1 and HSV2 (HerpesSimplex Virus type 1 and type 2), hCMV and mCMV (human and murinecytomegalovirus), VZV (varicella zoster virus), EBV (Epstein barr virus)HHV6 and HHV8 (human herpes viruses, types 6 and 8).

There is a need in the art to develop novel therapies for the treatmentand prevention of viral infections such as infections caused by theHerpes virus.

SUMMARY OF THE INVENTION

The present inventor has surprisingly demonstrated that bupropion isuseful for the prevention and treatment of viral infections. Inparticular, the inventor has shown that bupropion is useful for thetreatment and prevention of certain symptoms of viral infections causedby a herpes virus. More specifically, the inventor has shown bupropionis useful for the treatment of symptoms caused by a Herpes SimplexVirus. Bupropion is thus of potential benefit in the treatment ofinfections of viruses of the Herpes family or conditions caused thereby,particularly Herpes Simplex Virus (HSV) 1, HSV2, Herpes zoster andVaricella zoster.

Accordingly, the present invention provides a use of bupropion for themanufacture of a medicament for the prevention or treatment of a viralinfection. The present invention also provides a use of bupropion toprevent or treat a viral infection. The present invention furtherprovides a method of treating and preventing a viral infectioncomprising administering an effective amount of bupropion to an animalin need thereof.

Other features and advantages of the present invention will becomeapparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples while indicating preferred embodiments of the invention aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As hereinbefore mentioned, the present inventor has demonstrated thatbupropion is useful in the prevention or treatment of viral infections.The present inventor has shown that bupropion is superior to many otheranti-viral agents such as acyclovir and famciclovir in the treatment andprevention of infections caused by the herpes virus.

Accordingly, the present invention provides a use of bupropion or aphysiologically acceptable salt, solvate or enantiomer thereof for themanufacture of a medicament for the prevention or treatment of a viralinfection. The present invention also provides a use of bupropion or aphysiologically acceptable salt, solvate or enantiomer thereof toprevent or treat a viral infection. The present invention furtherprovides a method of treating and preventing a viral infectioncomprising administering an effective amount of bupropion or aphysiologically acceptable salt, solvate or enantiomer thereof to ananimal in need thereof.

The term “effective amount” as used herein is an amount effective, atdosages and for periods of time necessary to treat or prevent a viralinfection.

The term “animal” as used herein includes all members of the animalkingdom including humans.

The term “bupropion” as used herein includes all physiologicallyacceptable salts and solvates thereof and all enantiomers thereof.

The bupropion for use in the invention is suitably in the form of aphysiologically acceptable salt. This salt may include an acid additionsalt formed with organic or inorganic acids for example hydrochloride,hydrobromide, sulphate, nitrate, phosphate, formate, mesylate, citrate,benzoate, fumarate, maleate and succinate. Preferably, the bupropion isin the form of its hydrochloride salt. The chemical structure ofbupropion hydrochloride is shown below.

Bupropion for use according to the invention may be administered as theraw chemical comprising the active compound. Preferably, the bupropionis formulated into a pharmaceutically acceptable composition ormedicament. Conveniently, bupropion for use according to the inventionmay be formulated in conventional manner using one or morepharmaceutically acceptable excipients. Thus, bupropion for useaccording to the invention may for example be formulated for oral,sub-lingual, buccal, parenteral, rectal or intranasal administration orin a form suitable for administration by inhalation or insufflation(either through the mouth or nose).

For oral administration the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycollate);or wetting agents (e.g. sodium lauryl sulphate). The tablets may becoated by methods well known in the art.

Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents(sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters or ethyl alcohol); and preservatives (e.g.methyl or propyl P-hydroxybenzoates or sorbic acid).

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

Bupropion for use according to the invention may be formulated forparenteral administration by injection, conveniently intravenous, inintramuscular or subcutaneous injection. Formulations for injection maybe presented in unit dosage form e.g. in ampoules or in multi-dosecontainers, optionally with an added preservative.

The compositions for parenteral administration may take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilising and/ordispersing agents. Alternatively, the active ingredient may be in dryform such as a powder, crystalline or freeze-dried solid forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water orisotonic saline before use. They may be presented, for example, insterile ampoules or vials.

Bupropion for use according to the invention may also be formulated inrectal compositions such as suppositories or retention enemas, e.g.containing conventional suppository bases such as cocoa butter or otherglyceride. Tablets for sub-lingual administration may be formulated in aconventional manner.

For intranasal administration, bupropion for use according to theinvention may be used, for example, as a liquid in the form of a sprayor drops or as a powder. Suitably the preparation for intranasaladministration is delivered in the form of a spray or aerosol from aninsufflator or from a pressurised pack or nebuliser with the use of asuitable propellant.

For administration by inhalation, bupropion for use according to theinvention is conveniently delivered in the form of an aerosol spraypresentation from pressurised packs or a nebuliser, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of gelatin for use in an inhaler or insufflatermay be formulated containing a powder mix of a compound of use in theinvention and a suitable powder base such as lactose or starch.

Various formulations of bupropion have been disclosed in U.S. Pat. Nos.5,427,798, 5,358,970, 5,541,231, 5,731,000 and 5,763,493 (and otherpatents related to U.S. Pat. No. 5,358,970) all of which areincorporated herein by reference.

As indicated above, bupropion is of therapeutic and prophylactic benefitin the treatment of viral infections. In particular, bupropion is usefulin the prevention and treatment of infectious diseases and conditionscaused by viral infections. Such diseases include chicken pox (Varicellazoster), shingles (Herpes zoster), keratitis in rabbits, herpeticencephalitis in mice, cutaneous herpes in guinea pigs, cold sores(herpes labialis) and genital herpes (herpes simplex virus) in humans,retinitis, pneumonitis and keratitis in humans (hCMV), as well asdiseases caused by Epstein Barr Virus (EBV), human herpes virus 6 (HHV6), HHV 7 and HHV 8 and Human Immune deficiency Virus (HIV). Ofparticular mention are chicken pox, shingles, cold sores and genitalherpes in humans; of special mention are cold sores and genital herpesin humans.

The terms “treatment and prevention” include the prophylaxis, preventionof recurrence of symptoms and suppression or amelioration of symptoms(whether mild, moderate or severe) as well as the treatment ofestablished conditions caused by a viral infection.

It will be appreciated that the precise dose of bupropion administeredwill in general depend on the age and condition of the patient and thefrequency and route of administration and will be at the ultimatediscretion of the attendant physician. The compound may be administeredin single or divided doses and may be administered one or more times,for example 1 to 4 times per day, for one or two days.

Typically, bupropion is useful for the treatment and prevention of aviral infection in an amount between 0.1 mg to 1000 mg per day, morepreferably in an amount between 25 mg and 600 mg per day and mostpreferably in an amount between 150 mg to 300 mg per day. Preferably,the bupropion is given for at least two days.

Typically, pharmaceutical compositions comprise bupropion in the amountof 0.1 mg to 500 mg per unit dose, more preferably in an amount between25 mg and 300 mg per unit dose and most preferably in an amount between50 mg to 150 mg per unit dose.

The total amount of bupropion taken to prevent or treat a viralinfection or a particular episode of a recurrent viral infection istypically between about 50 mg and about 2000 mg, more preferably betweenabout 150 mg and about 1500 mg, most preferably between about 300 mg and1200 mg.

The bupropion may be administered in combination with other anti-viralagents that are useful in the treatment or prevention of a viralinfection, such as infections caused by a herpes virus.

The following non-limiting examples are illustrative of the presentinvention:

EXAMPLES

The following examples illustrate that demonstrate that bupropion iseffective in preventing and treating herpes virus infections.

Example 1

The first case treated was CR a 50 year old businessman with recurrentgenital Herpes Simplex viral infection. There were 5-6 recurrences peryear. Acyclovir was partially effective in aborting the attacks as theseverity of the attacks was reduced slightly the duration of the attackswas reduced from 2 weeks to 5-7 days. The subject took bupropion whichresulted in an alteration of the course of the attack and within 2 days,the attack was aborted. Since that time, whenever the subject feels thatan attack is about to commence, 4 doses of bupropion, each dosecontaining 150 mg of bupropion, are taken over 2 days and this eitheraborts the attack completely, or reduces it to a small crop of lesionswhich heal completely within 48 hours. There has not been a singlesignificant recurrence of the sort that existed, since commencing thisregime over one year ago.

Example 2

The second case was a 36-year-old nurse, DB. She developed HSV Iinvolving the right upper lip and nares (cold sores). She hasapproximately 1 episode per month related to menstrual periods. This hasbeen occurring for the last 6 years and has lasted for at least a weekof every month. The severity varied according to her general state ofhealth and stress levels. The outbreaks lasted at least one week andhave made a significant impact on her psychological state. She has notbeen on systemic therapy. Topical therapy does not change the durationof the lesions, but prevents the secondary infections that she is proneto without topical therapy.

The commencement of bupropion, 300 mg twice daily, for 2 days on day 2of an outbreak resulted in complete resolution of her lesions by the endof day 3. A minor recurrence of the lesions one week later was abortedby a similar dosage within the first day.

Example 3

The third case was GH, a 28-year-old entrepreneur. He has a coffee shopchain. He is thus very visible and he is very self-conscious of evenminor blemishes on his face. He has mild herpes labialis (cold sores),which occurs approximately 5 times a year. He has taken intermittentacyclovir and has even considered continuous acyclovir, because of hisimage. He is also aware when an attack is going to occur and takingacyclovir with the tingling has reduced his attacks to barely detectableand lasting 3 days. After taking 2 tablets of bupropion (each containing150 mg) when he feels the tingling, he has not had an eruption in thelast 3 months.

Example 4

The fourth case was JR, a 22-year-old student with extensive genitalherpes. He has had 4 attacks thus far, which have been treated initiallywith acyclovir and then later with famciclovir. The normal duration ofthese attacks on these agents was 5-7 days. He was unable to attendclasses and took a further 2 weeks before he felt normal. A big featureof his illness is the severe fatigue that precedes and follows hisattacks. The subject took bupropion, 300 mg twice daily, for 2 days andhe was feeling well. The lesions had cleared completely and they had notbeen as bad as usual. He had not developed any post-viraemia fatigueeither. He later used a further 2 day course when he felt tingling. Hedid not develop any eruptions at that time.

Example 5

The fifth case was SC, a 45-year-old medical secretary with recurrentherpes labialis. He had been paying for acyclovir privately, despite thecost, because of his wish to suppress his frequent and unsightlylesions. He had however, been getting breakthrough lesions on theacyclovir and he was concerned that his herpes had become resistant tothis agent. He took bupropion in combination with acyclovir with goodresults. An attack was treated within 24 hours on the two agents. Sincethen, he has had two further episodes where he felt tingling of the lip.He took bupropion, 150 mg every 12 hours for 2 days. No outbreak ofherpes labialis occurred with either of these episodes.

Example 6

The sixth case was AB, a 49-year-old reporter. He developed hypertensionand mild renal impairment on acyclovir. This was given for recurrentbuttock herpes simplex II. This was ceased and after 1 year, thehypertension and renal impairment reverted to normal. Famciclovirsuccessfully suppressed his disease, but he still had minor outbreaks oncontinuous therapy approximately once every 2-3 months. He startedtaking bupropion with onset of his pre-outbreak symptoms and he hasreported that he has not had an eruption since.

Example 7

The seventh case was AW a 26-year-old woman who from infancy hasdeveloped severe herpes labialis (cold sores) every 2 months. Thisinvolved the nares, upper and lower lips bilaterally. Even after topicalacyclovir, the course of the illness was 2 weeks of significantoutbreak. She took bupropion and within 36 hours of taking 300 mg, shedid not progress from her initial lesion on the left upper lip. Shedeveloped a rash—which prove to be scarlet fever. Her partner alsodeveloped scarlet fever as well. The lesion started disappearing after 3days and by day 5 was hardly noticeable. The scarlet fever did notworsen on the bupropion. It should be noted that this patient is usuallyvery intolerant of medications and tends to vomit easily. No sideeffects were noticed on bupropion.

Example 8

The eighth case that was treated with bupropion was a medicalreceptionist. Her normal herpes labialis lasted between 5 and 7 days.Topical therapy with acyclovir has been unhelpful in the past. Shedeveloped a lesion on the right side of her chin and was given bupropion150 mg twice daily for 2 days. Within 24 hours, the lesion had dried outand was scabbing within the next 12 hours. There was complete resolution3 days later.

The physician conducting the above trials has reported that the resultsthus far have been beyond expectation. He is commented that “not onlyhas there been a success from a completely unlikely agent, but there hasalso been a success beyond that achieved by the well-establishedanti-viral agents”.

While the present invention has been described with reference to whatare presently considered to be the preferred examples, it is to beunderstood that the invention is not limited to the disclosed examples.To the contrary, the invention is intended to cover variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

All publications, patents and patent applications are hereinincorporated by reference in their entirety to the same extent as ifeach individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

I claim:
 1. A method of treating or preventing a recurrence of a herpesviral infection comprising administering an effective amount ofbupropion or a physiologically acceptable salt, solvate or enantiomer ofbupropion to an animal in need thereof.
 2. A method according to claim 1wherein the herpes viral infection is caused by a virus selected fromthe group consisting of Herpes zoster, Herpes Simplex Virus type 1,Herpes Simplex Virus type 2, and Herpes labialis.
 3. A method accordingto claim 1 wherein the herpes virus is a herpes simplex virus.
 4. Amethod according to claim 3 wherein the herpes simplex virus is HerpesSimplex Virus type 1, HSV1.
 5. A method according to claim 1 wherein theherpes virus is Herpes labialis.
 6. A method according to claim 1wherein the bupropion is administered in an amount from about 0.1 mg toabout 500 mg per unit dose.
 7. A method according to claim 6 wherein thebupropion is administered in an amount from about 25 mg to about 300 mgper unit does.
 8. A method according to claim 6 wherein the bupropion isadministered in an amount from about 50 mg to about 150 mg per unitdose.
 9. A method according to claim 6 wherein the effective amount ofbupropion is from about 50 to 2000 mg.
 10. A method according to claim 9wherein the effective amount of bupropion is administered in at leasttwo doses.
 11. A method according to claim 9 wherein the effectiveamount of bupropion is administered in at least four doses.
 12. A methodaccording to claim 6 wherein the effective amount of bupropion is fromabout 300 to 1200 mg.
 13. A method according to claim 1 wherein theanimal is a human.
 14. The method according to claim 1 wherein theeffective amount of bupropion is formulated as an oral dosage form. 15.The method according to claim 1 wherein the bupropion is administered incombination with another antiviral agent.
 16. The method according toclaim 15 wherein the antiviral agent is acyclovir.